The present invention relates to new pharmaceutical formulations for the treatment of gastrointestinal disorders.
About 10% to 20% of people suffer once or several times in their life from a peptic ulcer of the stomach or of the duodenum or from other inflammatory gastrointestinal lesions. There are a wide variety of causes, for example including endogenous cytotoxic substances, such as gastric acid and bile acids, or exogenous factors, such as ethanol or medicaments. Thus, the gastrointestinal tract is among the organ systems which are most frequently affected by the side effects of medicaments. In particular, non-steroidal antiinflammatory agents lead to erosion and ulceration of the stomach.
At present, the treatment of mucosal damage (ulcers) of the stomach and of the duodenum is primarily based on the elimination of aggressive factors, such as
blocking acid and pepsin by acid neutralization (antacids, such as, for example, aluminum hydroxides, calcium carbon, hydrotalcite, magnesium hydroxide, sodium bicarbonate and others), inhibition of secretion (anticholinergics, H.sub.2 -antagonists, such as, for example, cimetidine or ranitidine, vagotomy or distal gastric resection) or increased rate of elimination (metoclopramide, sulpiride); and
prevention of cytotoxic effects of certain constituents (bile acids, lysolecithin) of the duodenal juice in the stomach by absorption (cholestyramine, antacids) or increased rate of elimination (metoclopramide, sulpiride).
In addition, film-forming agents, such as sulfated disaccharides (sucralfate), are used.
Thus, treatment to date is primarily based on a reduction in the activity of gastric acid and pepsin. This in intended to prevent the "breakthrough" of the mucosal barrier. However, the consequence of this treatment is that there are also adverse effects on the digestion of food, which in turn results in further disturbance of and strain to the gastrointestinal tract.
A number of other disadvantages of these therapeutic agents used nowadays are known. Thus, the acid gastric juice itself also has protective functions, for example in the resistance to bacteria. This natural protection is lost. Moreover, antacids, depending on their composition, can cause constipation or the formation of stones or inhibit the absorption of minerals and drugs. Anticholinergic agents and the recently very frequently used H.sub.2 -antagonists have similar effects and, moreover, bring about more extensive disturbances. These medicinal agents are absorbable and thus effective systemically throughout the body, and are associated with a large number of side effects. For example, anticholinergic agents bring about dry mouth and disturbances of accommodation; H.sub.2 -antagonists cause headaches, diarrhea, joint and muscle pain, fatigue, dizziness, loss of hair, sexual behavioral disturbances, liver damage and others.
It has also been proposed, in European Pat. No. 92,121, to cover the gastric mucosa with an amphoteric phospholipid surfactant in order to prevent damage. These considerations are based on the protective effect of natural surfactants in the lung. The nature of these "surfactants" has been examined in detail, for example: B. H. Hills et al., J. Appl. Physiol.: Environ. Exercise Physiol. 1982, 53 (1), 119-123; 1982, 53 (2), 463-469; 1983, 54 (2), 420-426; Respiration Physiology 1983, 51, 79-93; L. M. Lichtenberger, Scienced 219 (1983), 1327-1329.
The most important components which have been identified are:
dipalmitoylphosphatidylcholine (DPPC), PA1 dipalmitoylphosphatidylglycerol (DPPG), PA1 dipalmitoylphosphatidylethanolamine (DPPE) and PA1 sphingomyelin (SP). PA1 DPPC:DPPE:DPPG:SP (5:2:2:1) PA1 DPPC:DPPE:DPPG (5:2:2) PA1 DPPC:DPPE (1:1) PA1 DPPC:DPPG (1:1) or PA1 DPPC:DPPE:SP PA1 10-14% by weight of palmitic acid PA1 3-5% by weight of stearic acid PA1 8-12% by weight of oleic acid PA1 62-68% by weight of linoleic acid PA1 4-6% by weight of linolenic acid PA1 22-26% by weight of palmitic acid PA1 6-9% by weight of stearic acid PA1 8-12% by weight of oleic acid PA1 50-54% by weight of linoleic acid PA1 4-6% by weight of linolenic acid PA1 1-2% by weight of palmitic acid PA1 0-1% by weight of stearic acid PA1 8-12% by weight of oleic acid PA1 78-85% by weight of linoleic acid PA1 5-8% by weight of linolenic acid PA1 L=1, 4, 7, 8 or 10 PA1 m=0, 1, 2, 3 or 4 PA1 n=2 or 6 such as, for example, the following radicals EQU CH.sub.3 (CH.sub.2).sub.14 CO-- EQU CH.sub.3 (CH.sub.2).sub.16 CO-- EQU CH.sub.3 (CH.sub.2).sub.7 CH:CHCH.sub.2 (CH.sub.2).sub.6 CO-- EQU CH.sub.3 (CH.sub.2).sub.4 (CH:CHCH.sub.2).sub.2 (CH.sub.2).sub.6 CO-- EQU CH.sub.3 CH.sub.2 (CH:CHCH.sub.2).sub.3 (CH.sub.2).sub.6 CO-- EQU CH.sub.3 (CH.sub.2).sub.4 (CH:CHCH.sub.2).sub.4 (CH.sub.2).sub.2 CO-- PA1 20-10% by weight of palmitic acid PA1 5-4% by weight of stearic acid PA1 10-12% by weight of oleic acid PA1 62-68% by weight of linoleic acid PA1 3-6% by weight of linolenic acid PA1 22-26% by weight of palmitic acid PA1 7-9% by weight of stearic acid PA1 12-9% by weight of oleic acid PA1 54-50% by weight of linoleic acid PA1 5-6% by weight of linolenic acid PA1 1-3% by weight of palmitic acid PA1 0-2% by weight of stearic acid PA1 8-12% by weight of oleic acid PA1 85-75% by weight of linoleic acid PA1 6-8% by weight of linolenic acid, PA1 AS=phenylbutazone PA1 PL=phosphatidylcholine PA1 PC/CaCl.sub.2 =1,2-diacylglycero-3-phosphocholine/calcium chloride (content: 6.43% CaCl.sub.2) PA1 ASA=acetylsalicylic acid PA1 PL=phosphatidylcholine PA1 PC=1,2-diacylglycero-3-phosphocholine PA1 80% 1,2-diacylglycero-3-phosphocholine PA1 20% 1,2-diacylglycero-3-phosphoethanolamine.
Combinations, such as, for example,
are particularly advantageous.
However, in order to permit film formation, it is important (B. A. Hills et al., A.J. Physiol. 244 (Gastrointest. Liver Physiol 7), G561-G568, 1983) that the fatty acid radicals in the phospholipids are able to extend in a straight line. Thus, only saturated fatty acid radicals, in particular palmitic acid, are suitable.
However, the use of this type of "surfactant" for the therapy of mucosal damage involves a number of difficulties, as follows:
Much effort is involved in obtaining this type of natural surfactants of complex structure.
On therapeutic use of this type of surfactant, the predominantly saturated fatty acid radicals in the phospholipid must be regarded as a great problem because of their unfavorable effect on lipid metabolism and the risk of atherosclerosis resulting from this (M. Rosseneu et al., Atherosclerosis 32 (1979) 141-153).
The formation of a protective film in the stomach is very difficult. Extrapolation of the function of the surfactants in the pulmonary alveoli to the mucosa of the gastrointestinal tract is impossible because of the anatamical and physoilogical differences between the monolayer, flat endothelium which forms a good substrate for a stable molecular film of lipid. In respect of function, merely the exchange of small gas molecules (O.sub.2, CO.sub.2) takes place there, and these diffuse through the lipid film without difficulty.
In contrast, intensive secretion and absorption processes take place in the stomach and intestines. The latter processes relate, in particular, to large water-soluble molecules as well, so that film formation is hardly possible.
Present-day ulcer treatment is a symptomatic, and by no means curative, treatment. At the most, it cures the ulcer, but it does not cure the ulcerative disorder.
Thus, a treatment which increases the protective properties of the mucosa would be desirable as an alternative aim of treatment. The first active compound disclosed which stimulated the protective properties of the mucosa was carbenoxolone. However, because of pronounced side effects (retention of sodium and water, hypokaliemia), only restricted use is possible.
The properties of the prostaglandins which have been well documented experimentally, such as the increase in the secretion of bicarbonate and mucus, in the blood flow in the mucosa and in the promotion of epithelial cell maturation and of gastric emptying indicate that the therapeutic principle of cytoprotection would be fulfilled in an ideal manner by administration of this group of active compounds.
However, the long-lived PGE.sub.2 analogs which have been clinically tested to date were associated with the disadvantage of considerable systemic side effects.
In contrast, the natural prostaglandins act as so-called local hormones in the digestive tract as in other organs. This means that they do not reach their site of action via the blood stream but are formed in the immediate neighborhood of, or even directly in, the tissues in which they display their short-lived action.
Thus, it is worthwhile aiming at a therapeutic means of treatment which favors the physiological synthesis, locally in the intestinal mucosa, of the prostaglandins which protect the mucosa. From theoretical considerations, the substrates of prostaglandin synthesis which are particularly suitable for this are those which accumulate rapidly and persistently in the gastrointestinal mucosa on oral administration.
The object of the present invention is to make available pharmaceutical formulations for the treatment of gastrointestinal disorders, which accumulate rapidly and persistently in the gastrointestinal mucosa on oral administration and thus can be used as a substrate for the synthesis of protaglandins which protect the mucosa.